Hitherto, non-steroidal acidic anti-inflammatory agents such as acetylsalicylic acid, phenylbutazone, ibuprophen, indomethacin and the like have been widely used in the fields of surgery and internal medicine as analgesic and anti-inflammatory agents, with fairly satisfactory results. The pharmacological activity which is common to the non-steroidal acidic anti-inflammatory agents is inhibitory activity on the biosynthesis of prostaglandin; and this mechanism of action is considered to be that which induces the desired analgesic and anti-inflammatory activities, as reported by R. J. Flower et al., Biochemical Pharmacol., 23, 1439 (1974). In other words, the non-steroidal acidic anti-inflammatory agents only inhibit the biosynthesis of prostaglandin which is a factor for strengthening pain and inflammation in the living body; and, therefore, the analgesic and anti-inflammatory activities of these non-steroidal acidic anti-inflammatory agents are generally mild. [See, S. H. Ferreira, Nature, 240, 200 (1972)] Further, these agents have been reported as having serious side-effects such as gastrointestinal disorders and edema formation based on the inhibitory activity of prostaglandin biosynthesis. [See, P. W. Dodge et al., Anti-Inflammatory Drugs, edited by J. R. Vane and S. H. Ferreira, Springer-Verlag, p. 280, Berlin (1979)]
To solve such disadvantages of non-steroidal acidic anti-inflammatory agents, an extensive study has been made mainly from the standpoint of pharmaceutical preparations such as prodrugs, suppositories or preparations for external use in order to minimize or eliminate side-effects. That is, the most important problem regarding the existing non-steroidal acidic anti-inflammatory agents is how to utilize these agents most effectively.
In a series of studies on emorfazone, 4-ethoxy-2-methyl-5-morpholino-3(2H)-pyridazinone, the present inventors have found that emorfazone is a non-steroidal basic anti-inflammatory agent which does not inhibit the biosynthesis of prostaglandin; thus, emorfazone differs from the existing non-steroidal acidic anti-inflammatory agents. As a result of further studies, the present inventors have found that a combination of emorfazone and a non-steroidal acidic anti-inflammatory agent described above exhibits an excellent synergistic effect for analgesic activity and an additive or synergistic effect for anti-inflammatory activity, while the composition causes markedly decreased gastric disorders as a main side-effect inherent to the non-steroidal anti-inflammatory agents. Accordingly, the present invention is based on a finding that the dosage level of non-steroidal inflammatory agents can be decreased and simultaneously the toxicity and the side-effects inherent to these agents can be reduced by administering the non-steroidal acidic anti-inflammatory agents in combination with emorfazone.